The invention relates to a method for producing a particulate material from an at least partially liquid material containing a solvent and/or dispersant. The at least partially liquid material comprises, for example, a solution and/or a dispersion containing a liquid dispersant, i.e. a suspension and/or emulsion. The solvent and/or liquid dispersant preferably substantially comprises water but may also contain an organic component or at least partly comprise an organic solvent, for example tertiary butanol.
The method is intended in particular for the batchwise production of a particulate material from an at least partially liquid starting material which preferably contains at least one heat-sensitive component.
It is pointed out here that the freezing point of a solution usually depends on the concentration of the components of the solution and may be represented by a melting point diagram. On slowly cooling a solutionxe2x80x94depending on the initial compositionxe2x80x94frequently only one of the components is initially frozen and solidified, so that separation can take place. Aqueous solutions of active substances and excipients for drugs frequently have a eutectic temperature. On cooling a solution to or below the eutectic temperature, the solvent and a dissolved substance or possibly a plurality of dissolved substances are then simultaneously frozen and solidified, so that a eutectic mixture forms.
CH 664 005 A and the corresponding U.S. Pat. No. 4,608,764 A disclose various methods for the batchwise production of particulate materials. Inter alia, it was intended to freeze a solution and/or suspension in a container to give a block and to comminute this mechanically. The resulting particles were then fluidized, in the same container in which the freezing process was carried out, with, for example, process gas consisting of air and were at least for the most part dried by freeze-drying.
This method has various disadvantages. First, there is a considerable risk of separation during the freezing of a block. Furthermore, the mechanical comminution of a block formed by freezing a solution and/or suspension is complicated and expensive and easily leads to contamination of the material. Furthermore, experiments have shown that the freeze-drying by fluidization requires a fairly long time.
A further disadvantage of the known method is associated with the fact that, in the development of a novel product, usually only relatively small amounts are initially produced for test purposes and later on larger amounts of the product are produced as required, for the commercial utilization of the product. For the development and for the commercial production of a product, apparatuses of different sizes are therefore generally required, giving rise to high procurement costs. If a material is produced first in a small apparatus and then in a larger apparatus, new, optimal parameters of the method additionally have to be determined by experiments for this change of apparatus, which is often referred to as xe2x80x9cscale upxe2x80x9d. These additional experiments are time-consuming and increase the production costs.
U.S. Pat. No. 3,313,032 A discloses methods and apparatuses for the freeze-drying of originally liquid materials. In these processes, liquid material is sprayed in a container and the droplets formed are frozen to give particles. These are then dried by freeze-drying in a drying chamber which is formed by a region of the same container or arranged in another container. For fluidization and freeze-drying of the particles, process gas is passed upward from below through a region of the container. The process gas is sucked through a perforated base into the drying chamber and sucked out of the container through a filter arranged on one side of the container casing.
Experiments with other fluidized-bed driers, however, have shown that freeze-drying in a fluidized bed requires a great deal of time. In the case of the apparatus disclosed in U.S. Pat. No. 3,313,032, the containers which serve for freeze-drying are moreover evidently cylindrical from the perforated base to the filter, and the filter is only small in comparison with the cross-sectional area of the drying chamber. The freeze-drying can therefore be carried out only at low process gas flow rates, with the result that the drying time is additionally increased.
It is the object of the invention to avoid disadvantages of the known methods and apparatuses. It is intended to provide a method which makes it possible to form solid particles, rapidly, simply and as far as possible without separation, from an at least partially liquid material formed, for example, by a solution and/or suspension and/or emulsion, and then to dry said solid particles rapidly and economically at least to a great extent by freeze-drying, i.e. sublimation. Furthermore, it should preferably be possible to use one and the same apparatus alternatively for the production of small and relatively large amounts of a particulate material.
This object is achieved, according to the invention, by a method for the production of a particulate material from an at least partially liquid material containing a solvent and/or dispersant, the method being characterized in that the at least partially liquid material is atomized into droplets and these are frozen to particles by contact with a freezing fluid, that the particles are then dried by freeze-drying in a process chamber having a filter at the top, and that, during the freeze-drying, process gas is passed upward from below through the process chamber and through the filter in such a way that at least a substantial part of the particles rest against the filter during a substantial part of the freeze-drying taking place in the process chamber.
Advantageous further developments of the method are evident from the dependent claims.
According to the invention, at least a substantial part, namely preferably at least the greatest part, of the particles is thus caused, at least during a substantial part of the freeze-drying in a process chamber, to rest against a filter which is arranged at the top in the process chamber and in fact at least partly bounds said chamber at the upper end. The method makes it possible to pass the process gas at a relatively high flow rate and a correspondingly high velocity through the process chamber serving for freeze-drying. Because the particles rest against the filter, a water vapor envelope formed during drying of the particles and enclosing the latter and otherwise inhibiting heat transfer and material transport can furthermore probably be broken up by contact with the filter. The heat transfer to the particles and the release of water vapor are therefore better than in the case of particles suspended in the process gas. Furthermore, the or each gas-permeable filter element of the filter produces a pressure gradient, which in turn produces a high gradient of the water vapor pressure, which promotes the freeze-drying process. For all these reasons, the method according to the invention permits a substantial reduction in the time required for freeze-drying of a given amount of particles.
As already mentioned, the at least partially liquid starting material and the finished, particulate material may contain, for example, at least one heat-sensitive component. The at least partially liquid starting material and the finished, particulate material contain, for example, at least one therapeutic active drug substance and/or drug excipient for the formation of a drug for the treatment of humans and/or animals and/or at least one substance for diagnostic purposes. The active substance and/or excipient and/or the substance for diagnostic purposes are, for example, hydrophilic and water-soluble but may also form a dispersion, such as a suspension or emulsion, together with a liquid dispersant.
The at least partially liquid starting material and the finished material may contain, for example, as dissolved or dispersed component(s), at least one protein and/or peptide, such as an amino acid sequence, immunoglobulins, blood plasma proteins (e.g. a coagulation factor), amorphous and/or crystalline insulin, hirudin, erythropoietins, filgrastim, lenograstim, immunomodulators (e.g. alpha-, beta- and/or gamma-interferon and/or interleukin), peptide hormones, for example leuproline, leuprolide acetate, buserelin acetate, goserelin acetate, triptorelin, or immunosuppresives, such as, for example, cyclosporins. Further possible components are nucleases, enzymes, cytostatic agents, vitamins, vaccines, monoclonal and other antibodies, corticosteroids (e.g. triamcinolone diacetate), steroid hormones (e.g. testosterones), tumor suppression genes, antibiotics (for example penicillin G, erythromycin derivatives), neuroleptic drugs (for example clozapine, fluoxetine), anesthetics (e.g. methadone, morphine), Cox-2 inhibitors, cardiovascular drugs, liposomal formulations, microorganisms and/or cells (e.g. human or animal skin cells or stem cells). If the starting material contains microorganisms or (other) cells for the treatment of humans and/or animals, these can be dispersed, for example, in a dispersant consisting of a nutrient.
The solution or the other at least partially liquid starting material and the finished, particulate material can furthermore contain at least one hydrophilic drug excipient, for example mannitol or cyclodextrin or a polymer, such as polyvinylpyrrolidone, in addition to an active substance or possibly instead of an active substance.
The starting material and the finished, particulate material can also be provided for the formation of a rapidly soluble nutrient or at least nutrient additive or for any other use instead of being provided for human medicine or veterinary medicine.